Gene expression is accomplished by the transcription of genetic information from DNA to RNA and then the translation of RNA to protein molecules. In transcription, RNA molecules are synthesized by using the base sequence of one strand of DNA as a template in a polymerization reaction that is catalyzed by RNA polymerases. RNA polymerases bind to a DNA strand at particular sites called promoters.
Transcriptional regulation is one mechanism of controlling gene expression. Some promoters are competent to support initiation by RNA polymerase, although repressor proteins may act to prevent the initiation process. In other cases, the polymerase itself is not adequate and ancillary proteins (e.g. transcription factors) are necessary for initiation to occur.
Hematopoiesis (i.e., blood cell development) involves complex transcriptional and translational controls. Pluripotent stem cells in the bone marrow divide to form committed precursor cells, which mature along distinct pathways. The different types of blood cells are produced in different numbers, and the production of each must be regulated individually to meet changing needs. An understanding of these controls is still very incomplete.
A central objective in the study of hematopoiesis is the isolation of factors governing cell commitment to differentiation along a specific lineage. In several other systems, transcription factors have been shown to play a role in cellular differentiation. More recently, transcription factors have also been implicated in normal myeloid (monocytic, neutrophilic) differentiation and in the etiology of myeloid leukemia.
Since the late 1970's, progress has been made toward the development of general methods for introducing cloned gene sequences into eukaryotic cells (e.g., mammalian cells). As a result, genetic therapies whereby heterologous genes are introduced into, and expressed by host cells, are now possible. However, to date, little is known about the factors governing cell commitment in hematopoiesis because hematopoietic stem cells have proven difficult to genetically engineer. For example, most promoters, particularly retroviral promoters, become repressed after being introduced into hematopoietic stem cells. Therefore, heterologous genes which are under the control of heterologous promoters are not expressed.